DESCRIPTION (Verbatim from the application): The regulation of cerebral blood flow occurs primarily at the blood vessel-brain parenchyma interface and depends on a complex array of chemical and electrical stimuli that, under physiologic conditions, couple cerebral blood flow to neuronal activity. It has been proposed that potassium ions lost by neuronal cells during action potential repolarization may affect vessel diameter by acting on inward rectifier channel mechanisms expressed in vascular smooth muscle cells. We have recently demonstrated a novel mechanism of potassium-induced vasodilatation that implies activation of "metabolic channels," normally shut down by intracellular ATP (K(ATP)). We propose to investigate in detail the relevance of such a mechanism in vitro and in vivo. In addition, we and others have shown that expression of potassium channels involved in the regulation of cerebral blood flow and in the control of extracellular ion homeostasis are compromised following traumatic brain injury or ischemia. We therefore propose to investigate how the loss of these mechanisms can impact cerebrovascular function in neurological disease. The underlying hypothesis of this proposal is that, in the brain, activation of K(ATP) not only mediates changes caused by oxygen deprivation, but is also responsible for potassium-mediated vasodilatations occurring during normal oxygen supply and therefore during normal neuronal activity. The Specific Aims of our proposals are: 1) To investigate in vitro the ion channel mechanisms involved in potassium-mediated vasodilatation. 2) To elucidate the mechanisms of potassium-mediated dilations in vivo. These studies will allow better understanding on neuronal-vascular interactions and will open new perspectives for the treatment of neurological diseases.